Metabolic Dysfunction-Associated Fatty Liver Disease and Fibrosis Status in Patients with Type 2 Diabetes Treated at Internal Medicine Clinics: Türkiye DAHUDER Awareness of Fatty Liver Disease (TR-DAFLD) Study

Background/Aims: This awareness study aimed to determine the ultrasound (US) examination rates in relation to US-confirmed metabolic dysfunction-associated fatty liver disease (MAFLD) diagnosis in internal medicine outpatients with type 2 diabetes (T2D) across Türkiye. Materials and Methods: A total of 6283 T2D patients were included in this multicenter retrospective cohort study conducted at 17 internal medicine clinics across Türkiye. The presence and indications for US performed within the last 3 years were recorded along with US-confirmed MAFLD rates, laboratory findings on the day of US, and referral rates. Fibrosis-4 (FIB-4) index was calculated to estimate the risk of advanced liver fibrosis (FIB-4 index ≥ 1.3). Results: Overall, 1731 (27.6%) of 6283 patients had US examination, which revealed MAFLD diagnosis in 69.9% of cases. In addition, 24.4% of patients with US-confirmed MAFLD were at risk of advanced fibrosis (FIB-4 index ≥ 1.3), and the referral rate was 15.5%. Conclusion: In conclusion, our findings emphasize an insufficient MAFLD awareness among clinicians and the likelihood of most of T2D patients to be at risk of living with an unknown status regarding their MAFLD and advanced fibrosis risk.


INTRODUCTION
Type 2 diabetes (T2D) and fatty liver disease share common pathophysiological mechanisms and their co-existence is mutually detrimental, as each condition increases the development and progression of the other. 1,2Nonalcoholic fatty liver disease (NAFLD) refers to fatty infiltration of the liver in the absence of significant alcohol consumption and other chronic liver diseases. 1,36][7] Accordingly, MAFLD is defined by the presence of fatty liver (hepatic steatosis) plus at least 1 of the 3 criteria, including T2D, overweight/obesity, or evidence of metabolic dysfunction. 5nce, in contrast to NAFLD which is a diagnosis of exclusion, MAFLD diagnosis does not require the exclusion of excessive alcohol consumption or other chronic liver diseases. 2,5All T2D patients with hepatic fat content >5% identified by radiological imaging modalities, biological scores with reasonable accuracy or biopsy are considered to have MAFLD. 7,8[11][12][13] Screening T2D patients for MAFLD is considered a costeffective strategy, given that T2D patients with concomitant MAFLD represent a highly prevalent and an exceptionally high-risk group within the MAFLD population. 2,7[15] This seems to be the major challenge given the majority of T2D patients with MAFLD are asymptomatic at early stages where internal medicine and endocrinology specialists may play a pivotal role in recognition of the disease as they assess these patients at the frontline. 2,14,15 the setting of T2D, presence of MAFLD simply requires the demonstration of >5% hepatic fat without the nuisance of ruling out other chronic liver diseases, which might actually facilitate the diagnosis of the disease by the non-hepatologist. 7,8,16Hence, improved awareness of clinicians about the risk and clinical relevance of MAFLD in the setting of T2D is considered to be of utmost importance in fighting this global health challenge, by enabling early identification and appropriate and timely intervention of high-risk MAFLD patients, since even the advanced fibrosis stage is considered potentially reversible upon reversal of the initial injurious stimuli. 2,12in Points

Referral Rates in Patients with Ultrasound-Confirmed Metabolic Dysfunction-Associated Fatty Liver Disease
Overall, referral for further investigation upon detection of MAFLD on US was performed in 185 (15.5%) of 1190 patients with available data.Referral rates in patients at risk of advanced fibrosis were 17.9% (Table 1).

DISCUSSION
Our findings in a retrospective cohort of 6283 T2D patients revealed insufficient awareness among internists regarding the screening or case-finding strategy for MAFLD in the setting of T2D.Less than one-third of T2D patients had US examination during their followup at internal medicine clinics, which confirmed the presence of MAFLD in 69.9% of cases.Advanced fibrosis risk (FIB-4 index ≥1.3)was evident in 24.4% of patients at the time of US-confirmed MAFLD, while the referral for further investigation was performed in 15.5% of patients.
Türkiye is considered a risky region in terms of NAFLD burden with an estimated 30% prevalence of NAFLD (range, 48.3%-60.1%),which is expected to further increase with rising prevalence of obesity and T2D. 18The transabdominal ultrasonography findings from the recent Cappadocia Cohort Study of Türkiye in 2797 subjects (14% with T2D) revealed a high prevalence of hepatic steatosis (60.1%) emphasizing that Türkiye is one of the leading countries in the world for NAFLD. 19e rates of US-confirmed MAFLD (69.9%) and advanced fibrosis risk (24.4%) in our patients are in line with consideration of MAFLD to affect over half of T2D patients (up to 75%-90%, possibly), and presence of histological hepatic fibrosis alongside steatosis in approximately 1 in 5 individuals with MALFD. 7,8,16,20In a meta-analysis of studies in T2D patients, the global prevalence of MAFLD by US imaging was estimated to   be 55.5%, while NASH (i.e., nonalcoholic steatohepatitis) and advanced fibrosis rates on biopsy were 37.3% and 4.8%, respectively. 20 4][15] Although most guidelines such as American Association of Clinical Endocrinology and American Association for the Study of Liver Diseases, European Association for the Study of the Liver, European Association for the Study of Diabetes and European Association for the Study of Obesity clinical practice guidelines and World Gastroenterology Organization global guidelines recommend a screening or case-finding strategy for MAFLD for at-risk patients including those with T2D, the implementation of these screening strategies in clinical practice is strongly limited by controversies regarding the diagnostic tests and treatment options for MAFLD. 9-13,21-24More importantly, due to low awareness and poor recognition of MAFLD among clinicians, many T2D patients living with MAFLD are considered to be unaware of their fibrosis stage, and those with advanced fibrosis remain at risk of advanced liver disease due to delayed referral to specialists for evaluation and care. 14,25Notably, the MAFLD and advanced fibrosis risk findings achieved in our cohort reflect the current status only in one-third of the overall study population, indicating that most patients with T2D had no US examination during their routine follow-up and thus were living with an unknown status regarding the MAFLD and advanced fibrosis risk.
Hence, our findings indicate the possible underdiagnosis of MAFLD in T2D patients treated at internal medicine clinics, emphasizing a need for increased awareness among clinicians regarding the high prevalence of MAFLD and risk of advanced fibrosis in T2D patients, as well as the likelihood of US imaging and FIB-4 index to be used as a simple screening strategy in these patients.
Indeed, as surveillance for liver disease complications is recommended only for patients with severe fibrosis, application of more specific criteria for risk prediction (i.e., FIB-4 and US-determined indices) for referring patients to a hepatologist is considered a cost-effective fatty liver referral pathway, enabling more reasonable referral rates consistent with the underlying advanced fibrosis. 12,21,26Otherwise, the process may reveal very high referral rates (33-85%) when referral was applied also for T2D patients with less severe liver disease, despite the physician can continue the standard diabetes care including lifestyle modification in these patients with no need for further referral. 12,21In our cohort, with use of these stringent criteria (US plus FIB-4 index), 24.4% of MAFLD patients were found to be at risk of advanced fibrosis (FIB-4 scores ≥3) and the overall referral rate was 15.5%.The advanced fibrosis risk and referral rates in our study should be interpreted in the light of the possibility of including a larger population of patients at high risk of liver disease progression by definition of MAFLD.The likelihood of underestimating the mild disease in the present study should also be considered, given the exclusion of newly diagnosed T2D patients and the low performance of US for the detection of mild steatosis, since it necessitates the presence of steatosis in at least 12.5%-33% of hepatocytes to detect fatty liver with optimal accuracy. 8,9,20,21 a recent study, based on the data from the U.S. National Health and Nutrition Examination Survey in 6727 T2D patients, MAFLD was identified in 4982 patients, which was classified as MAFLD(+)/NAFLD(−) in 2032 patients and MAFLD(+)/NAFLD(+) in 2950 patients. 16The new definition (MAFLD) was reported to increase the fatty liver diagnosis in T2D patients by 68.9%, while patients classified as MAFLD(+)/NAFLD(−) were also found to be at a higher risk of major adverse cardiovascular events, advanced fibrosis, all-cause and cardiovascular-related mortality compared to those classified as MAFLD(+)/ NAFLD(+). 16Accordingly, MAFLD not only identifies more patients due to no exclusion of other chronic liver diseases but also seems to be better in identifying patients at risk of liver and cardiovascular complications, which is considered to indicate a need for better risk stratification to prevent an over-inclusion of fatty liver. 16,27though there are no pharmacological agents approved specifically for treating MAFLD, lifestyle modification, particularly weight reduction via dietary and exercise strategies or bariatric surgery, in addition to statins and some antidiabetic medications (i.e., pioglitazone, glucagon-like peptide 1 receptor agonists and SGLT2 (i.e., sodium-glucose cotransporter-2) inhibitors) with proven benefits in overall improvements in liver histology and hepatic fibrosis are recommended in T2D patients with MAFLD. 2,7,8,10,28,29Thus, MAFLD is suggested to be considered an emerging diabetic complication and to be timely diagnosed and systematically evaluated by proactive participation of all health care providers taking care of T2D patients, as in other conventional diabetes-related complications. 2,8,12[35] Given that international guidelines increasingly advocate multidisciplinary approaches for patients with MAFLD, the strategies to fight against the underestimation of the disease burden and lack of awareness should also consider the potential interdisciplinary differences in awareness, knowledge and management of MAFLD and thus specifically target the medical specialties where the largest improvements could be made. 23,33,36e major strength of this study seems to be the potential generalizability of our results given the inclusion of 6283 T2D patients from 17 internal medicine clinics across Türkiye.However, certain limitations should be considered.First, due to the cross-sectional design, it is impossible to establish any cause-and-effect relationships.Second, since this is an awareness study regarding the US examination and MAFLD diagnosis rates in T2D patients, analysis of patient and treatment characteristics (i.e., family history, concomitant obesity, viral hepatitis, treatment changes in those with MAFLD/advanced fibrosis) was not within the scope of the study.Third, the unknown MAFLD status in most patients due to the absence of US imaging is another potential limitation.Fourth, the exclusion of newly diagnosed T2D patients and the use of US as the sole imaging modality might have resulted in an underestimated diagnosis of mild disease.Nevertheless, this study was conducted in the context of an awareness-raising project to provide a snapshot of the current MAFLD status among T2D patients treated at internal medicine clinics across Türkiye.
In conclusion, our findings revealed the favorable utility of US plus FIB-4 index in case-finding for MAFLD and identification of advanced fibrosis risk with reasonable referral rates in T2D patients treated at internal medicine clinics.However, this simple imaging-scoring algorithm, despite enabling the diagnosis of MAFLD in ~70% of patients and the risk for advanced fibrosis in ~25% of those with MAFLD, had been applied only in one-third of patients and with an indication of suspected MAFLD only in half of them, indicating that most patients with T2D were living with an unknown status regarding the MAFLD and advanced fibrosis risk.Hence, the possible underdiagnosis of MAFLD in T2D patients treated at internal medicine clinics emphasizes a need for increased awareness among clinicians on the high prevalence and significant hazards of MAFLD, necessitating its timely diagnosis in T2D patients, and the convenience of US plus FIB-4 index as an easy-to-use strategy in this regard.

Figure 1 .
Figure 1.Ultrasound examination and metabolic dysfu nctio n-as socia ted fatty liver disease rates in patients with type 2 diabetes.

Figure 2 .
Figure 2. Metabolic dysfu nctio n-as socia ted fatty liver disease; rates and advanced fibrosis status in patients with type 2 diabetes.